PROJECT SUMMARY Since the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago, the prognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhood cancers, many of which were uniformly fatal in the pre-chemotherapy era, is now 84%. Progress for a number of childhood cancers, however, has been limited, with approximately 50% of children with acute myelogenous leukemia, 50% of children with high-risk neuroblastoma, and more than 90% of children with brainstem glioma, still succumbing to their disease. In the US, cancer remains the leading cause of death from disease in children greater than one year of age. Moreover, the late effects of cancer treatment, including permanent organ and tissue damage, hormonal and reproductive dysfunction and second cancers, are of special concern, with more than 40% of the estimated 360,000 survivors of childhood cancer experiencing a significant health related quality of life complication from childhood cancer and its treatment. Thus, despite our advances, development of new therapeutic approaches must be a priority for childhood cancer basic, translational and clinical researchers. The Children's Oncology Group (COG), the world's largest organization devoted exclusively to childhood and adolescent cancer research, was founded 17 years ago. The COG's multidisciplinary research team, comprised of more than 9,000 members, conducts research at more than 220 leading children's hospitals, universities, and cancer centers. This proposal is for COG, as part of the National Cancer Institute's (NCI) National Clinical Trials Network (NCTN), to continue its collaborative research work that supports the mission of improving the outcome for all children with cancer. The COG will design and conduct clinical-translational studies for children with cancer that builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highest potential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseases, we will study novel therapeutic approaches including but not limited to targeted small molecule drugs, immunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trials focused on improving the quality of life children with cancer and survivors. As more than 90% of children diagnosed with cancer in the US are treated at COG member institutions, the COG has the ability to offer a diverse population of children with cancer and their families the opportunity to participate in innovative research. This research effort includes allowing for collection and annotation of biospecimens from all children with cancer, providing the foundation for discovery and accelerating the most promising research efforts conducted in laboratories around the world. The proposal is for support of the COG Network Operations Center, clinician- scientists who develop and conduct research, and for member sites to participate through enrollment of eligible subjects.